The growth and progression of prostate cancer are dependent on androgens and AR (androgen receptor). The major function of AR in the prostate is to regulate the proliferation and survival of prostate cells and this function is mediated by the ability of AR to modulate gene expression. While many androgen-regulated genes have been identified in the prostate, few have been shown to play a pivotal role in prostate cancer cell growth and progression. This led us to postulate that gene products not yet identified may be important in mediating the AR effects on cellular proliferation. Through gene array studies in LNCaP cells, we identified sGC11 as a novel androgen-regulated gene, whose expression level is directly related to prostate cancer cell proliferation. We base this on several key observations from our laboratory. First, siRNA knock-down of sGC11 severely compromised the proliferation of both androgen-dependent and -independent LNCaP cells. Secondly, sGC11 expression in androgen-independent cells is high and androgen unresponsive. Finally, sGC11 over- expression in androgen-dependent cells is sufficient for reproducing their androgen-induced growth. In addition, preliminary expression data using prostate tissues show that sGC11 is highly expressed in malignant androgen-dependent prostate cancer, and this is significantly elevated beyond this in advanced androgen- independent prostate cancer. Our overall hypothesis is that sGC11 is an important component of AR action in prostate carcinogenesis. Accordingly, the specific aims of this proposal are to (1) study the role of sGC11 in the proliferation, apoptosis, and tumorigenesis of prostate cancer cells, (2) elucidate the signaling pathway that is responsible for pro-proliferative actions of sGC11 in prostate cancer cells, (3) study the mechanism of androgen regulation of sGC11 expression in prostate cancer cells, and (4) measure the expression of sGC11 during the progression of prostate cancer. In view of the importance of AR in the development and progression of prostate cancer, the identification of sGC11 as a novel androgen-regulated gene may provide an important tool for studying the role of androgens and AR in prostate carcinogenesis. Because of its implicated role in the proliferation of prostate cancer cells and recently identified anti-p53 activity, sGC11 may be very important in the initiation and progression of prostate cancer and thus be a potential target of future cancer therapies. PUBLIC HEALTH RELEVANCE: Prostate cancer is the second leading cause of death among men, undergoing a transition from the treatable hormone-dependent to the usually lethal hormone-refractory. The androgen receptor and regulatory factors are key factors in both stages of prostate cancer. We have identified sGC11 as a novel androgen-regulated gene important for the proliferation of both androgen-dependent and, more importantly, androgen-independent prostate cancer cells, and we propose here study the role of sGC11 in the growth and tumorigenesis of prostate cancer cells.